Antisense technology is an effective means for reducing the expression of one or more specific gene products and can therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications. Chemically modified nucleosides are routinely used for incorporation into antisense sequences to enhance one or more properties such as for example affinity and nuclease resistance. One such group of chemically modified nucleosides includes substituted α-L-bicyclic nucleoside wherein the furanose ring is replaced with a bicyclic furanose core having at least one further substituent.
Various bicyclic nucleic acids (BNA) have been prepared and reported in the patent literature as well as in scientific literature, see for example: Singh et al., Chem. Commun., 1998, 4, 455-456; Koshkin et al., Tetrahedron, 1998, 54, 3607-3630; Wahlestedt et al., Proc. Natl. Acad. Sci. U.S.A., 2000, 97, 5633-5638; Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222; Wengel et al., PCT International Application WO 98-DK393 19980914; Singh et al., J. Org. Chem., 1998, 63, 10035-10039, the text of each is incorporated by reference herein, in their entirety. Examples of issued US patents and published applications include for example: U.S. Pat. Nos. 6,770,748, 6,268,490 and 6,794,499 and published U.S. applications 20040219565, 20040014959, 20030207841, 20040192918, 20030224377, 20040143114 and 20030082807; the text of each is incorporated by reference herein, in their entirety.
BNAs have also been reported in the scientific literature having the L configuration (α-L-BNA or α-L-LNA) wherein most of these α-L-BNA's have been studied in oligomeric compounds, see for example: Gaubert, G. et al., Nucleosides Nucleotides Nucleic Acids 2003, 22, 1155-1157; Kumar et al., J. Org. Chem. 2006, 71, 4188-4201; Fluiter et al., Chem Bio Chem, 2005, 6, 1-6; Arzumanov et al., Oligonucleotides, 2003, 13, 435-453; Frieden et al. Nucleic Acids Res., 2003, 31(21), 6365-6372; Sorensen et al., J. Am. Chem. Soc. 2002, 124, 2164-2176; Petersen et al., J. Am. Chem. Soc. 2001, 123, 7431-7432; Rajwanshi et al., Angew Chem Int Ed Engl 2000, 39, 1656-1659; Rajwanshi et al., J. Chem. Commun. 1999, 1395-1396; and U.S. Pat. No. 7,053,207; the text of each is incorporated by reference herein, in their entirety.
Consequently, there remains a long-felt need for agents that specifically regulate gene expression via antisense mechanisms. Disclosed herein are substituted α-L-bicyclic nucleosides that are useful in the preparation of antisense compounds for modulating gene expression pathways, including those relying on mechanisms of action such as RNaseH, RNAi and dsRNA enzymes, as well as other antisense mechanisms based on target degradation or target occupancy. One having skill in the art, once armed with this disclosure will be able, without undue experimentation, to identify, prepare and exploit antisense compounds for these uses.